「血管新生」(angiogenesis)在動物體的生長發育過程中扮演著許多相當重要的角色，所以血管新生的的過程發生問題則會對動物體造成相當大的影響，產生和血管方面相關的疾病，而血管新生的調控機制主要是利用（促血管生成因子）和（抑制血管生成因子）的相互調節控制。近來，相當多的研究指出腫瘤的生長和轉移必須依賴新血管的生成，而抑制腫瘤產生新的血管則能夠抑制腫的生長和轉移，因此藉由抑制血管新生的方式來抑制腫瘤生長儼然成為治療癌症的新策略。TNP-470是黴菌代謝物fumagillin的衍生物，具有相當抑制血管新生的活性，能又有效的抑制內皮細胞的生長、分裂、移動、以及形成管狀構造，加上有較低的毒性，目前TNP-470已經進入藥物發展的人體臨床測試第三期了。然而，TNP-470的效力顯著，但對於TNP-470抑制血管新生的作用機轉了解的卻相當有限；僅知會停止內皮細胞的細胞週期運行，阻斷內皮細胞的生長，此外還有研究發現TNP-470會抑制細胞週期調控因子Rb的磷酸化，以及透過p53和p21來影響內皮細胞的生長。而在我們的實驗中發現TNP-470處理過的內皮細胞其細胞週期調控因子cyclin D1蛋白有增加的趨勢，而我們在內皮細胞內大量表現cyclin D1基因，使細胞內產生大量的cyclin D1蛋白，確實會增加TNP-470抑制內皮細胞生長的活性。因此，我們更進一步的去探討這cyclin D1蛋白在TNP-470抑制內皮細胞生長的作用機轉中所扮演的角色；包括TNP-470對和cyclin D1相互作用的蛋白、cyclin D1的酵素活性、細胞內的位置方面的影響做進一步的探討。然而，我們發現在TNP-470處理過的內皮細胞中除了有較高處理過的內皮細胞中除了有較高cyclin D1蛋白的表現外，也會使cyclin D1蛋白增加與其一起形成功能性蛋白復合物的這些其他蛋白間的交互作用，但是這樣增加交互作用卻反而抑制了這個功能性蛋白的酵素活性。此外，有研究指出在老化的細胞中存在較多的cyclin D1蛋白，我們更進一步發現TNP-470會透過讓內皮細胞老化而達到抑制期生長的過程。此外，我們更進一步的去測量TNP-470是否會在內皮細胞產生產生活性養物質 (ROS) 因而產生氧化壓力造成細胞中的DNA受損，但是並沒有發現在TNP-470的刺激下內皮細胞有較高ROS產生。希望藉由我們的研究能夠提供一些線索，能夠更了解TNP-470抑制內皮細胞生長的作用機轉。

Angiogenesis plays multiple roles in both physiological and pathological condition. Recently, a lot of studies demonstrate that angiogenesis is essential for tumor growth and metastasis. Based on the critical role of angiogenesis in tumor growth, inhibition of angiogenesis may provide a promising therapy for cancer treatment. TNP-470, an analog of fumagillin, was reported to have a potent anti-angiogenic activity and has been entering the phase III of human clinical trial for the cancer therapy. Although several studies have shown that TNP-470 induced cell cycle arrest at G1 phase via p53 and p21, the involvement of other cell cycle mediators in mediation of anti-angiogenic effect of TNP-470 are not known. Western blotting analysis indicated that TNP-470 not only did induce the expression of p53 and p21 but also that of cyclin D1 in the bFGF-treated human endothelial cells (HUVEC). Moreover, transient overexpression of cyclin D1 increased the susceptibility of human endothelial cells to TNP-470. Since proteolysis and subcellular localization of cyclin D1 plays a determinant role in cell cycle progression from G1 to S, western blotting analysis, immunoprecipitation, immunofluorescence staining, cell fractionation and in vitro kinase assay were utilized to address the role of the stabilized cyclin D1 protein and its subcellular location in TNP-470-treated endothelial cells. Here, we found TNP-470 increased cyclin D1 protein accumulation and the association with its partner protein-CDK4 and p21, but repressed the enzyme activity of cyclin D1-dependent CDK4 in HUVEC. Furthermore, measurement of β-galactosidase activity in acidic pH showed that TNP-470 increased the senescence-like phenotype in HUVEC. The production of reactive oxygen species (ROS) known to involve senescence was not increased by TNP-470. In summary, up-regulation of cyclin D1 possibly via changing its associated partners and induction of senescence, participates in part the cytostatic effect of TNP-470 in endothelial cells.

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